Impact of Accidental High or Low Implantation Depth on Peri-Procedural Outcomes after Implantation with the Self-Expanding ACURATE neo2

Background: Precise implantation could play a crucial role in the technical success of transcatheter aortic valve replacement (TAVR) for some prostheses. The impact of an accidental implantation depth (ID) outside the recommended range has not been assessed for the ACURATE neo2 (NEO2). Methods: Data from 1839 patients with severe native aortic stenosis treated with the NEO2 prosthesis were evaluated. We compared the results of prostheses implanted in an ID both inside and outside the recommendations. The outcome assessment followed the Valve Academic Research Consortium-3 criteria. Results: Patients were retrospectively divided into high (<3 mm; n = 412), optimal (3–7 mm; n = 1236), and low (>7 mm; n = 169) implantations. Technical success (94.7% vs. 94.7% vs. 91.7%, p = 0.296) and device success were high (90.1% vs. 89.3% vs. 84.6%, p = 0.112) without differences between groups. Rates of relevant paravalvular regurgitation (PVL; >mild or VinV due to PVL) were comparable (1.2% vs. 1.8% vs. 1.2%, p = 0.759). Even when hemodynamics were superior in the high-implantation group, with greater iEOA (1.01 cm2/m2 vs. 0.95 cm2/m2 vs. 0.92 cm2/m2, p < 0.001), spontaneous embolization or after post-dilatation was more common. Low implantation was associated with a higher rate of associated pacemaker implantation (PPI) (6.1% vs. 8.8% vs. 14.8%, p = 0.001). Conclusions: Implantation with the ACURATE neo2 showed excellent hemodynamic results, including low gradients and a small number of relevant PVL, in line with a high technical success rate that was irrespective of the ID. A favorable outcome can also be achieved in accidental low or high positions. Low implantation was associated with a higher rate of associated pacemaker implantation. Deliberately high implantation should be avoided due to the risk of embolization.


Introduction
Transcatheter aortic valve replacement (TAVR) represents the gold standard in the treatment of elderly patients with high-grade aortic valve stenosis (AS).There has been steady improvement in transcatheter heart valves (THVs) over the years, but precise implantation of the prosthesis could be a key factor in the technical success of the procedure.
In recent years, clinical research has focused on the implementation of standardized implantation concepts such as the cusp-overlap technique to achieve optimal prosthesis implantation depth (ID) [1].The influence of ID on the conduction system and the rate of permanent pacemaker implantation (PPI) for commercially available prostheses have been well examined [2][3][4].In contrast, data on prosthesis-specific effects on hemodynamic parameters, such as the occurrence of paravalvular leakage (PVL) and prosthesis-patient mismatch (PPM), are scarce [5].Each prosthesis has a specific landing zone, as defined in the corresponding instructions for use (IFU).The optimal position in the annulus is usually analyzed in in vitro benchmark tests.However, ID depends on many factors and can be difficult to control in practice.Accidentally high or low implantation of prostheses impacts hemodynamic results, pacemaker rates, coronary access, and embolization rates [6][7][8].Adverse events, as well as relevant outcome variables, were mentioned according to the Valve Academic Research Consortium-3 criteria [9].Therefore, we aimed to analyze to what extent the self-expanding (SE) ACURATE neo2 (NEO2) tolerates an accidental ID outside the recommended landing in a real-world population and what impact it has on hemodynamics and clinical performance.

Patient Cohort
A total of 1839 patients undergoing transfemoral TAVR with the NEO2 valve (Boston Scientific, Marlborough, MA, USA) between December 2016 and July 2023 at two German high-volume TAVR centers were included retrospectively.Patients with primary bailout valve-in-valve (VinV) procedures were excluded (n = 22).Comorbidities, risk scores, and data on echocardiography, multidetector computed tomography (MDCT), and cardiac catheterization were recorded as baseline characteristics in a dedicated database, as were procedural data and complications.Supplemental follow-up data were collected from outpatient visits, from recent physician reports, or by telephone interview.The study was conducted in accordance with the Declaration of Helsinki.Due to the retrospective nature of this study and the anonymous data processing, ethical approval was waived by each local ethics committee.Patients approved anonymous data collection.

Multidetector Computed Tomography
Multidetector computed tomography (MDCT) was performed with a 64-slice or a 192-slice dual-source scanner (Somatom Definition or Somatom Force, Siemens Healthcare, Forchheim, Germany), as previously described [10].Analysis of MDCT datasets was accomplished by using dedicated software (3mensio Structural Heart version 10.6, Pie Medical, The Netherlands).The aortic valve calcium score (AVCS) was measured according to the Agatston method using non-contrast-enhanced MDCT scans [11].Relevant left ventricular outflow tract (LVOT) calcification or the presence of eccentric aortic valve calcification was determined by a visual assessment of the aortic valve in short-axis views.The cover index is defined as: 100 × [(THV diameter − perimeter derived annulus diameter)/THV diameter].

Device Description
The technical features of the NEO2 have already been described [12].Compared with its predecessor (ACURATE neo), the prosthesis has a larger external sealing skirt to mitigate PVL.

Definition and Measurement of Implantation Depth
The manufacturer recommends a landing zone corridor for SE NEO2.All prostheses were initially intended to be implanted in the recommended landing zone.Assessment of the ID was performed retrospectively in the cusp-overlap view (Figure 1).We rated the implantation based on the measured ID < 3 mm as high, between 3 and 7 mm as recommended, and >7 mm as low (Figure 2).

Definition and Measurement of Implantation Depth
The manufacturer recommends a landing zone corridor for SE NEO2.All prostheses were initially intended to be implanted in the recommended landing zone.Assessment of the ID was performed retrospectively in the cusp-overlap view (Figure 1).We rated the implantation based on the measured ID < 3 mm as high, between 3 and 7 mm as recommended, and >7 mm as low (Figure 2).

Outcomes
The primary outcome measures were technical success, device success (30 days), and hemodynamic performance (PVL, PPM, effective orifice area [EOA], and mean gradients) according to the Valve Academic Research Consortium 3 (VARC3) criteria [9].Secondary outcome measures were procedural duration and contrast amount, as well as in-hospital events, according to VARC 3. PVL was assessed by the respective echocardiography laboratory and graded according to VARC3 as none/trace, mild, moderate, or severe.

Statistical Analysis
Statistical analyses were conducted using R (version 4.2.1, 2021; R Foundation for Statistical Computing, Vienna, Austria).Continuous data are provided as mean (SD) or median (IQR), and categorical variables as frequencies, as appropriate.Comparison of multiple groups was accomplished using the Tukey-Kramer post hoc test for normally distributed variables or otherwise with Benjamini-Hochberg correction, as indicated.The p-value for trend was calculated with a Pearson-test for normally distributed variables or, otherwise, with a Spearman-test for non-normally distributed variables.The Mantel-Haenszel test was used for categorical variables.Additional univariate and multivariable logistic regression analyses were performed to evaluate the impact of ID on specific clinical or echocardiographic events (PVL, PPM, and PPI).Covariates with a p-value < 0.01 in univariate regression were included in the multivariate model.For all analyses, a twosided p-value < 0.05 was considered significant.

Outcomes
The primary outcome measures were technical success, device success (30 days), and hemodynamic performance (PVL, PPM, effective orifice area [EOA], and mean gradients) according to the Valve Academic Research Consortium 3 (VARC3) criteria [9].Secondary outcome measures were procedural duration and contrast amount, as well as in-hospital events, according to VARC 3. PVL was assessed by the respective echocardiography laboratory and graded according to VARC3 as none/trace, mild, moderate, or severe.

Statistical Analysis
Statistical analyses were conducted using R (version 4.2.1, 2021; R Foundation for Statistical Computing, Vienna, Austria).Continuous data are provided as mean (SD) or median (IQR), and categorical variables as frequencies, as appropriate.Comparison of multiple groups was accomplished using the Tukey-Kramer post hoc test for normally distributed variables or otherwise with Benjamini-Hochberg correction, as indicated.The p-value for trend was calculated with a Pearson-test for normally distributed variables or, otherwise, with a Spearman-test for non-normally distributed variables.The Mantel-Haenszel test was used for categorical variables.Additional univariate and multivariable logistic regression analyses were performed to evaluate the impact of ID on specific clinical or echocardiographic events (PVL, PPM, and PPI).Covariates with a p-value < 0.01 in univariate regression were included in the multivariate model.For all analyses, a two-sided p-value < 0.05 was considered significant.

Discussion
The impact of an ID outside the recommended landing zone on outcome and hemodynamics after implantation with the SE NEO2 prosthetic valve is unclear, as data on this topic are scarce.Therefore, we investigated to what extent the NEO2 tolerates IDs outside of the recommended landing zone and what effect the ID has on hemodynamics and outcome.
The main findings of the present study are: (1) NEO2 shows excellent hemodynamic results, including low gradients and even low rates of relevant PVL, which is in line with the high technical success rate; this was found to be irrespective of ID; (2) Accidental high implantation of the prosthesis showed slightly improved hemodynamics in terms of EOA and severe PPM and reduced the need for PPI; (3) Accidental low implantation resulted in a higher rate of severe PPM and PPI; (4) The risk of valve embolization was high in too low or high implantations.

Procedural Performance
The SE supraannular ACURATE neo2 THV has emerged as a prosthesis with excellent hemodynamic properties and a low rate of PPI [12,13].Nevertheless, the precise implantation of the device itself also plays a prominent role regarding procedural outcome and hemodynamics.The SE NEO2 is implanted using a top-down technique.After precise positioning at the target level, the stabilization arches are released first, followed by the stent body itself.Despite precise positioning of the marker at the target level, factors like calcification of the native annulus as well as aortal kinking or aortic angle, which can both lead to an unpredictable force on the delivery catheter, might influence the final ID [14,15].In this context, recent studies have analyzed the effects of rapid pacing during implantation on more precise and optimized ID, which might be an option in difficult anatomies [1,15].Embolization occurred in a total of 22 cases, in 17 cases spontaneously or after post-dilatation, and in 5 cases due to mechanical complications such as wire problems or during device detachment.Among cases with spontaneous embolization and known primary ID, the implantation was too high (n = 6) or too low (n = 4) in 71.4% (n = 10/14) of the cases, see Supplemental Table S1.The higher rate of post-dilatation in high-implanted valves in our study might be explained by the higher rate of primary paravalvular leakage due to impaired sealing in the native annulus or to secure the valve position to avoid embolization.

Hemodynamic Outcome
While some studies reveal a positive correlation between ID and the rate of PVL with early-generation SE THVs, we were not able to confirm this with the NEO2 [16].This may be due to the general decrease in PVL after adapting the prosthesis design and adding a skirt in third-generation prostheses [12,13,17].The most recent comparisons between different SE THVs no longer show a correlation between ID and the occurrence of PVL and confirm our results showing generally low rates of relevant PVL (1.2-1.8%)[18].An analysis of the hemodynamics of the Neo family in small annuli revealed an increased risk of PPM for implantation at low ID [19].Event rates in high-or low-implantation may be influenced by differences in the baseline characteristics, such as, for example, eGFR, LVEF, mean gradient, or EuroScore II.However, multivariable regression analyses fail to show an independent association of ID with moderate or severe PPM, whereas data on balloon-expandable prostheses show a positive correlation between ID and the risk of PPM [20].The fact that EOA decreases with increasing ID is in contrast to the lack of an effect of ID on post-interventional gradients.This might be related to the general problem of echocardiographic assessment of post-interventional hemodynamics [21].Analyses of the impact of PVL and PPM on long-term survival currently have not produced consistent results [22].However, the Scope I trial found no difference regarding mortality over the long term, despite an increased rate of PVL with the predecessor, the ACURATE neo [23].

Permanent Pacemaker Implantation
Generally, low implantation, short membranous septum (MS), preexisting right bundle branch block (RBBB), and AV block I are known predictors of the necessity for PPI [3,5,18].A patient-specific ID according to the length of the MS (MIDAS; Minimizing Depth According to the membranous Septum) has been shown to reduce the rate of PPI with the Medtronic Evolut THV system [24].In addition, the cusp-overlap technique has proven to be valuable, as this view has shown a high ID most accurately at the level of the MS for the Medtronic Evolut THV, although these results have not been confirmed for the ACURATE neo [1,25].Overall, the NEO 2 is well known for its low PPI rates due to the special stent design and the low radial force [26].In line with this, our results show a range of PPI rates between 6.1% and 14.8%, depending on ID.The right bundle branch block as well as the ID are proven to impact the PPI rate in multivariable analysis, irrespective of differences in the baseline characteristics.

Coronary Access
High implantation with supraannular, long-stent frame SE devices impairs future coronary access [6,27,28].In our study, periinterventional coronary obstruction occurred in only one patient (0.6%).The topic of future coronary access with respect to the ID of the NEO 2 systems has to be evaluated further, especially in the context of future VinV options.More recently, a modified implantation strategy that focuses on the correct anatomical rotation has been applied in practice.This has further reduced the risk of acute coronary obstruction and facilitated access to future coronary interventions [29,30].

Limitations
The present study should be viewed in light of some limitations: its retrospective, non-randomized nature; the absence of external monitoring of adverse events; the lack of core laboratory analysis of imaging data such as the echocardiographic assessment of PVL; the visual assessment of LVOT calcification and eccentric aortic valve calcification without further quantification; and the fact that the ID was measured angiographically and not by computed tomography.

Conclusions
The self-expanding ACURATE neo2 shows excellent hemodynamic results, including low gradients and low rates of relevant PVL in line with high technical success rates.Interestingly, these favorable results were also consistent for final positions outside the recommended landing zone, including accidental low and high positions.Deliberately high implantation should be avoided due to the risk of device embolization.

Figure 2 .
Figure 2. Schematic showing implant depth (ID) according to aortic annulus.Illustration of the ACURATE neo2 in the native aortic annulus in relation to the ID.The center of each image (left; upper right; lower right) of the prosthesis is copyrighted by the manufacturer (© 2023 Boston Scientific Corporation (Marlborough, MA, USA) or its affiliates.All rights reserved).

Figure 2 .
Figure 2. Schematic showing implant depth (ID) according to aortic annulus.Illustration of the ACURATE neo2 in the native aortic annulus in relation to the ID.The center of each image (left; upper right; lower right) of the prosthesis is copyrighted by the manufacturer (© 2023 Boston Scientific Corporation (Marlborough, MA, USA) or its affiliates.All rights reserved).

Table 1 .
Baseline characteristics according to implantation position.

Table 2 .
Procedural outcomes and complications according to implantation position.